Many advanced cancers such as renal cell carcinoma and squamous cell carcinoma of the lung have proven particularly refractory to chemotherapy. It is therefore warranted to test new agents or new experimental modalities in such tumors. Animal studies suggest that chemotherapeutic activity of certain chemotherapeutic agents can be augmented by the use of dimethylsulfoxide (DMSO). Patients with metastatic squamous cell carcinoma of the lung were therefore treated with DMSO and cyclophosphamide. Fourteen patients were treated with 5 or 6% DMSO over 3 days and 1500 mg/m2 of cyclophosphamide. Serial blood and urine samples were collected to assess pharmacokinetics of cyclophosphamide. No antitumor responses were seen although 9/14 patients had stabilization. Toxicity was mainly hematologic similar to cyclophosphamide alone. The plasma pharmacokinetics of cyclophosphamide in this study are similar to previously reported results for cyclophosphamide alone but the 24 hour urinary excretions of cyclophosphamide is lower than previously reported. The low order of clinical responsiveness in this tumor suggest that other antineoplastic agents or more sensitive tumors should be tested.